Project Summary The administration of drugs like insulin requires continuously variable delivery. This is because blood glucose is itself continuously varying, and the insulin requirement parallels the amount of glucose in the blood. The only clinically used method to permit continuously variable deliver of therapeutic proteins like insulin is a pump. Pumps can vary therapeutic delivery but they do so at a high cost: a physical connection of the outside of the patient, where the drug reservoir resides, and the inside of the patient, where drug absorption will ultimately take place. This connection in the case of insulin pumps is a cannula or needle, which can be dislodged, crimped, snagged, infected and most importantly, rapidly gets biofouled after implantation. This leads to variable and unpredictable delivery. Instead, we are developing the Photoactivated Depot or PAD approach and applying it to insulin use. With the PAD approach, an insulin containing material is injected into the skin, just like regular insulin, but remains there inactive until a light source that is outside the body stimulates the injected material through the skin with light to release insulin. Our first generation PAD designs linked insulin to a polymer via a light-cleaved linker. When a pulse of light from an LED illuminates this material, insulin is released, and the amount released is proportional to the amount of light. We have demonstrated that these materials work in diabetic animals to release insulin and reduce blood glucose. Despite this success, these first generation materials have performance that makes them untenable for human use. Specifically, the linked polymer that is used to insure that insulin stays at the site of injection makes up >90% of the material, meaning that the total insulin present is less than what is needed for human efficacy. In addition, the low density of insulin means that the rate of photo-cleavage is also insufficient. Because of this, we are proposing multiple approaches to address these issues. In Specific Aim 1 we are creating multiple new PAD materials that eliminate the polymer required in our first generation materials, and in so doing create much higher density materials that are 90% insulin. In Specific Aim 2 we are incorporating new light-cleaved linkers that will release insulin using higher wavelengths of light. This will increase the amount of light that reaches the depot, and hence the ease of insulin release, because longer wavelengths of light penetrate tissues more easily. Finally, in Specific Aim 3 we are closely examining these new materials for their ability to control blood glucose in diabetic animals. By executing these three aims, we anticipate creating a new and revolutionary approach to continuously variable protein delivery, one that minimizes invasiveness, and maximizes the close matching of therapeutic with patient requirements. Relevance The successful completion of the proposed work will create a new method to administer insulin that effectively eliminates most of the injections normally required or the need of a pump and reduces variationsinbloodsugar.Thishasthepotentialtoimproveboththequalityoflifeandthequalityof healthofdiabeticswhodependoninsulintolive.